In normal tissue, the stroma provides an inhibitory barrier to restrict epithelial cell growth. While this barrier function remains in early tumor development, it can be reversed during later stages of tumorigenesis, and the stroma subverted or "activated" to participate in tumor development. How this process occurs is not known, but is thought to involve changes in the stromal fibroblasts, the predominant cell type in the stroma, which produce and modify the stromal extracellular matrix (ECM). One reason that we know so little about stromal activation is that we lack a suitable physiologic experimental system. To that end, we have developed a novel in vivo-like 3D stromal system derived from fibroblasts at progressive stages of cancer development. In initial comparisons of normal and tumor-associated stroma, we have observed structural and biochemical alterations in both fibroblasts and their secreted ECMs. Based on these preliminary data, we hypothesize that altered attachment signaling within the activated stromal fibroblasts contributes to the tumor promoting properties of the tumor-associated stroma. We also propose that inhibiting these signals can block cancer progression by restoring the tumor-repressive property of normal stroma. To test these hypotheses, we propose 2 aims. Aim 1 will test the hypothesis that alterations in the integrin-dependent Src and FAK signaling pathway are critical to the development of tumor-promoting stroma. Aim 2 will test the hypothesis that epithelial tumor-cell invasion can be repressed by targeting the fundamental stromagenic signaling pathways. The completion of the proposed studies should assist us to better understand the process of stromal activation, and provide insights into how to manipulate the process to contain epithelial tumor transformation or cause tumor regression. Ultimately, our long-term goal is to target the tumor-associated stroma thus maintaining cancer as an innocuous chronic disease. [unreadable] [unreadable] [unreadable]